"The antimetabolites have been used for the treatment of childhood cancer for more than 40 years. This class of agent continues to play a critical role in the treatment of childhood leukemia. The primary objective of this project is to study the clinical pharmacology of antimetabolites and other anti-leukemic agents to determine if they are being utilized optimally, and to develop rational, pharmacological-based alternative therapeutic approaches to the treatment of childhood leukemia." "In our current lower risk ALL trial, we are applying observations made in our preclinical studies showing that thioguanine (TG) is 10-fold more potent than mercaptopurine (MP) against leukemic cell lines and lymphoblasts from patients with ALL. Pharmacodynamic correlation between plasma TG and RBC TG-nucleotide levels, and measures of drug toxicity and disease outcome, are being investigated. Results of this trial and the clinical pharmacologic assessment of TG has guided the design of the current CCG phase 3 randomized trial comparing TG to MP in the lower risk ALL population." "We are also exploring a new class of antimetabolite specific for thymidylate synthetase (TS). ZD1694, a classical antifol which is a potent inhibitor of TS, is currently being evaluated in a pediatric phase 1 trial and pharmacokinetic study. A novel and sensitive enzyme inhibition assay for TS inhibitors has been developed and is being evaluated." "Methotrexate is an antimetabolite widely used in pediatric cancer, and when administered in high doses must be followed by the rescue agent leucovorin. We are studying carboxypeptidase-G2, (CPDG2) a recombinant enzyme capable of hydrolyzing MTX into inactive metabolites. CPDG2 may offer distinct advantages over leucovorin in certain clinical situations. Based on our pre-clinical investigations, nationwide protocols have been developed to treat patients with severe renal dysfunction following HDMTX with CPDG2. To date, more than 60 patients with renal failure have been treated, with the enzyme producing a > 98% decrease in MTX concentrations within 15 minutes of administration."